This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our previous work and that of others clearly demonstrate the important role cholesterol plays in the replication of HIV. We have shown that a cholesterol-sequestering agent betacyclodextrin holds significant promise as an HIV microbicide. The importance of cholesterol in HIV biology to this point has been based on the role this lipid plays in membrane biology, including the fusion of biological membranes. Over the last year we have obtained evidence that cholesterol may have a direct effect on HIV transcription as well. Our results indicate that a transcription factor whose expression is co-regulated with that of genes related to cholesterol synthesis directly activates HIV gene transcription. These results indicate that cholesterol levels in cells and tissues may impact HIV replication at the level of gene transcription. Furthermore, the results have significant implications for lipodystrophy associated with the use of anti-retroviral drugs some of which profoundly disturb lipid homoestasis. The paradoxical effects of statins on HIV release and HIV protein synthesis may also be explained in part by this novel observation. These studies have been carried out in both cell lines and primary cells confirming the potential importance of this observation in vivo.